KSHV-encoded miRNAs target MAF to induce endothelial cell reprogramming

Hansen, Amy J.; Henderson, Stephen; Lagos, Dimitrios; Nikitenko, Leonid L.; Coulter, Eve; Roberts, Sinead; Gratrix, Fiona; Plaisance, Karlie; Renne, Rolf; Bower, Mark; Kellam, Paul; Boshoff, Chris

doi:10.1101/gad.553410

Cited by 154 publications

(138 citation statements)

References 54 publications

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“…Thus far, miRNA studies have been constrained by sensitivity limits for detection of individual miRNAs and for the discovery of miRNA-target interactions. Targets with functions that seem to befit the biology of B cell development, endothelial cell differentiation, and KSHV (such as BACH1, xCT, MAF, and others) have been individually validated (132)(133)(134). These are by no means the only targets, and it is anticipated that additional targets will be identified in the future.…”

Section: Viral Mirnas Support Viral Infection and Latent Persistencementioning

confidence: 99%

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Dittmer

Damania

2016

Journal of Clinical Investigation

181

152

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Section: Viral Mirnas Support Viral Infection and Latent Persistencementioning

confidence: 99%

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Dittmer

Damania

2016

Journal of Clinical Investigation

181

152

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“…It has been reported that KSHVinfected LECs show an up-regulation of genes associated with BECs. 4,23 We examined the LEC-to-BEC transcriptome reprogramming present in our array data to confirm that the KSHV infection For personal use only. on April 27, 2019. by guest www.bloodjournal.org From had been successful.…”

Section: Kshv Introduces Tumor Traits and Migration Potential Into Lymentioning

confidence: 99%

“…It has been reported that KSHVinfected LECs show an up-regulation of genes associated with BECs. 4,23 We examined the LEC-to-BEC transcriptome reprogramming present in our array data to confirm that the KSHV infection had been successful. By calculating the transcriptome distances between sample groups, we confirmed that KSHV-infected LECs were closer to BECs than parental LECs (supplemental Figure 1C).…”

Section: Kshv Introduces Tumor Traits and Migration Potential Into Lymentioning

confidence: 99%

The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility

Wu¹,

Hu²,

Chen³

et al. 2011

Blood

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miRNAs have emerged as master regulators of cancer-related events. miRNA dysregulation also occurs in Kaposi sarcoma (KS). Exploring the roles of KS-associated miRNAs should help to identify novel angiogenesis and lymphangiogenesis pathways. In the present study, we show that Kaposi sarcoma-associated herpesvirus (KSHV), the etiological agent of KS, induces global miRNA changes in lymphatic endothelial cells (LECs). Specifically, the miR-221/miR-222 cluster is down-regulated, whereas miR-31 is upregulated. Both latent nuclear antigen (LANA) and Kaposin B repress the expression of the miR-221/miR-222 cluster, which results in an increase of endothelial cell (EC) migration. In contrast, miR-31 stimulates EC migration, so depletion of miR-31 in KSHV-transformed ECs reduces cell motility. Analysis of the putative miRNA targets among KSHV-affected genes showed that ETS2 and ETS1 are the downstream targets of miR-221 and miR-222, respectively. FAT4 is one of the direct targets of miR-31. Overexpression of ETS1 or ETS2 alone is sufficient to induce EC migration, whereas a reduction in FAT4 enhances EC motility. Our results show that KSHV regulates multiple miRNAmRNA networks to enhance EC motility, which eventually contributes to KS progression by promoting the spread of malignant KS progenitor cells. Targeting IntroductionKaposi sarcoma-associated herpesvirus (KSHV) was identified in 1994. 1 KSHV is also associated with 2 other human B-cell leukemias, primary effusion lymphoma (PEL) and multicentric Castleman disease. 2 Kaposi sarcoma (KS) is one of the few human cancers derived from a lymphatic endothelial cell (LEC) lineage, 3,4 and typically appears as colored lesions or patches on the skin, although it can spread to internal organs. 2 This disease has been recognized as a highly disseminated and angiogenic tumor. 4 Analyzing KSHV clonality at different stages of KS has shown that KS begins as a polyclonal disease and then evolves into a mono/oligoclonal disease involving infected spindle cells. 5 This model therefore implies that the spreading of a few malignant spindle cells in patients' bodies occurs during tumor progression. Moreover, distal metastasis, such as pulmonary KS, can be observed in AIDS-KS patients and causes diffused lung disease. Tumor cells of KSHV-associated B-cell neoplasias (PEL and multicentric Castleman disease) are also able to migrate into body cavities. 6 The ability of KSHV to induce cell migration and invasion is therefore important to disease progression.In vitro, KSHV infects both micro-and macrovascular endothelial cells (ECs), and these cells are useful when studying the role of KSHV in the pathogenesis of KS. 7,8 KSHV has also become a powerful tool that aids in the study of EC biology. 9 KSHV infects both LECs and blood vessel ECs (BECs) of microvascular origin in vitro. 3,4 After infection, KSHV stimulates EC invasiveness by inducing extracellular matrix metalloproteinases (MMPs) such as MMP-1, MMP-2, and MMP-9. 10 Because the majority of cells in KS lesions and in KSHV-infected...

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“…Thus far, viral miRNAs have been identified in a number of DNA viruses, including members of the herpesvirus, polyomavirus, and adenovirus families (3)(4)(5). These viral miRNAs have been described to regulate their replication cycles (6, 7) and the cellular transcriptome (5,(8)(9)(10), and even to mimic endogenous miRNAs (11,12).…”

mentioning

confidence: 99%

Engineered RNA viral synthesis of microRNAs

Varble

Chua

Perez

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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MicroRNAs (miRNAs) are short noncoding RNAs that exert posttranscriptional gene silencing and regulate gene expression. In addition to the hundreds of conserved cellular miRNAs that have been identified, miRNAs of viral origin have been isolated and found to modulate both the viral life cycle and the cellular transcriptome. Thus far, detection of virus-derived miRNAs has been largely limited to DNA viruses, suggesting that RNA viruses may be unable to exploit this aspect of transcriptional regulation. Lack of RNA virus-produced miRNAs has been attributed to the replicative constraints that would incur following RNase III processing of a genomic hairpin. To ascertain whether the generation of viral miRNAs is limited to DNA viruses, we investigated whether influenza virus could be designed to deliver functional miRNAs without affecting replication. Here, we describe a modified influenza A virus that expresses cellular microRNA-124 (miR-124). Insertion of the miR-124 hairpin into an intron of the nuclear export protein transcript resulted in endogenous processing and functional miR-124. We demonstrate that a viral RNA genome incorporating a hairpin does not result in segment instability or miRNA-mediated genomic targeting, thereby permitting the virus to produce a miRNA without having a negative impact on viral replication. This work demonstrates that RNA viruses can produce functional miRNAs and suggests that this level of transcriptional regulation may extend beyond DNA viruses.

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KSHV-encoded miRNAs target MAF to induce endothelial cell reprogramming

Cited by 154 publications

References 54 publications

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility

Engineered RNA viral synthesis of microRNAs

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